title: Ahp cyclodepsipeptides: the impact of the Ahp residue on the "canonical inhibition" of S1 serine proteases.
abstract: S1 serine proteases are by far the largest and most diverse family of proteases encoded in the human genome. Although recent decades have seen an enormous increase in our knowledge, the biological functions of most of these proteases remain to be elucidated. Chemical inhibitors have proven to be versatile tools for studying the functions of proteases, but this approach is hampered by the limited availability of inhibitor scaffold structures with the potential to allow rapid discovery of selective, noncovalent small-molecule protease inhibitors. The natural product class of Ahp cyclodepsipeptides is an unusual class of small-molecule canonical inhibitors; the incorporation of protease cleavage sequences into their molecular scaffolds enables the design of specific small-molecule inhibitors that simultaneously target the S and S' subsites of the protease through noncovalent mechanisms. Their synthesis is tedious, however, so in this study we have investigated the relevance of the Ahp moiety for achieving potent inhibition. We found that although the Ahp residue plays an important role in inhibition potency, appropriate replacement with β-hydroxy amino acids results in structurally less complex derivatives that inhibit serine proteases in the low micromolar range.
authors.affiliation: Chemical Biology, Zentrum für Medizinische Biotechnologie, Fakultät für Biologie, Universität Duisburg-Essen, Universitätsstrasse 2, 45117 Essen, Germany.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Stolze
authors.forename: Michael
authors.initials: M
authors.lastname: Meltzer
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
authors.forename: Markus
authors.initials: M
authors.lastname: Kaiser
mesh_terms: D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D010881:Piperidones / Q000737:chemistry*; D011485:Protein Binding; D057057:Serine Proteases / Q000737:chemistry / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C555955:3-amino-6-hydroxy-2-piperidone; D047630:Depsipeptides; D010881:Piperidones; D015842:Serine Proteinase Inhibitors; D057057:Serine Proteases
keywords: Ahp cyclodepsipeptides; canonical conformations; inhibitors; serine proteases; structure-activity relationships